Abstract
Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. However, when used orally significant gastrointestinal side effects and lack of overall efficacy were documented. Recently, in a phase II trial in Brazil for the treatment of temozolomide (TMZ)-resistant malignant gliomas, POH was well tolerated when administered intranasally. The present study explores the effects and mechanisms of POH on TMZ-sensitive and TMZ-resistant glioma cells. In vitro studies showed that POH was cytotoxic to TMZ-resistant as well as TMZ-sensitive glioma cells, and this effect was independent of O(6)-methylguanine-DNA methyltransferase expression. POH induced cytotoxicity, in part, through the endoplasmic reticulum (ER) stress pathway as shown by the increased expression of glucose-regulated protein-78 (GRP78), activating transcription factor 3, and C/EBP-homologous protein. In addition, POH impeded survival pathways, such as mTOR and Ras. As well, POH reduced the invasive capacity of sensitive and resistant glioma cells. POH alone and/or in combination with other ER stress-inducing cytotoxic drugs (i.e., 2, 5-dimethyl-celecoxib, nelfinavir) further induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. To show whether intranasal delivery of POH was effective for the treatment of TMZ-resistant gliomas, animals bearing intracranial tumors were given POH intranasally. Animals treated through intranasal administration of POH exhibited a decrease in tumor growth and an increase in survival. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally.
Highlights
Perillyl alcohol (POH) is a naturally occurring monoterpene that has been used orally for the treatment of a variety of cancers, including breast, pancreas, and lung carcinomas [1,2,3]
The results showed that treatment with POH at 1.5 mmol/L resulted in an increased expression of endoplasmic reticulum (ER) stress markers C/EBPhomologous protein (CHOP) and glucose-regulated protein-78 (GRP78) in each of the cell lines tested (Fig. 4A)
The results showed that POH increased CHOP, ATF3, PARP, and GRP78 in TMZ-resistant glioma cells
Summary
Perillyl alcohol (POH) is a naturally occurring monoterpene that has been used orally for the treatment of a variety of cancers, including breast, pancreas, and lung carcinomas [1,2,3]. Once GBMs become resistant to TMZ, there are very limited treatment options available. Patients with deep midline or subcortical GBMs had a better response than cortical GBMs [6] This is cogent, as patients with cortical GBMs are often surgically resectable, whereas the subcortical and deep GBMs are much more limited in surgical options and depend on adjunctive therapy for treatment. The studies presented here show that POH was cytotoxic to a variety of glioma cell lines, including several TMZ-resistant ones, without significantly affecting normal cells. POH was effective in reducing the growth of TMZ-resistant gliomas and increasing survival. Intranasal Delivery of Perillyl Alcohol for Glioma Therapy in vivo appear to be a combination of increased ER stress– mediated tumor cytotoxicity, decreased angiogenesis, and decreased tumor invasive capacity
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